RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE,KARNATAKA.

PROFORMA FOR REGISTRATION OF DISSERTATION

TOPIC:

A COMPARATIVE STUDY OF EQUIPOTENT DOSES OF INTRATHECAL CLONIDINE AND DEXMEDETOMIDINE ON CHARACTERISTICS OF BUPIVACAINE

SPINAL BLOCK

Dr.JAHNABEE SARMA

POST GRADUATE

DEPARTMENT OF ANAESTHESIOLOGY

K.V.G MEDICAL COLLEGE,

SULLIA.

Rajiv Gandhi University of Health SciencesKarnataka, Bangalore

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATE AND ADDRESS Dr JAHNABEE SARMA

POST GRADUATE STUDENT

DEPARTMENT OF ANAESTHESIOLOGY K.V.G MEDICAL

COLLEGE AND HOSPITAL KURUNJIBHAG SULLIA – 574327

2. NAME OF THE INSTITUTION K.V.G MEDICAL COLLEGE, SULLIA.

3. COURSE OF STUDY AND SUBJECT M.D. ANAESTHESIOLOGY

4. DATE OF ADMISSION TO COURSE 31-5-2011

5. TITLE OF TOPICA COMPARATIVE STUDY OF EQUIPOTENT DOSES OF INTRATHECAL CLONIDINE AND DEXMEDETOMIDINE ON CHARACTERISTICS OF BUPIVACAINE SPINAL BLOCK.

6 BRIEF RESUME OF THE INTENDED WORK

6.1 Need For the study

Spinal anesthesia is the most commonly used technique for lower abdominal and lower limb surgeries as it is very economical and easy to administer. Adrenaline being the first and latest being dexmedetomidine.

Intrathecal α2 agonist when used as adjunct potentiates the effect of local anaesthetics and allows a decrease in required doses. 4-6.

Clonidine is a partial α2 agonist used intrathecally with well established efficacy and safety. 7 It prolongs duration of motor and sensory spinal blockade2-4 when used along with local anaesthetics. Dexmedetomidine is new highly selective ά2 adrenoceptor agonist    and has been approved by Food and Drug Administration (FDA) as intravenous sedative and coanalgesic drug. Its ά2/ά1 selectivity is eight times higher than clonidine7.

On the basis of previous studies9-12, our hypothesis was that intrathecal dexmedetomidine 5 µg or clonidine 50 µg would be equipotent and would produce a similar effect on the characteristics of bupivacaine spinal anesthesia. The purpose of this study was to compare the onset and duration of sensory and motor block, as well as the hemodynamic changes and level of sedation, following intrathecal bupivacaine vs. intrathecal bupivacaine supplemented with low dose of either dexmedetomidine or clonidine.

6.2 Review of the Literature:

1) In a study done by Dobrydnjov I et al. where they used 6mg of 0.5% heavy

bupivacaine with 15µg Vs 30µg of clonidine for unilateral spinal anaesthesia in

unilateral inguinal hernia surgeries and showed it have produced excellent post

operative analgesia. They concluded that on adding clonidine 15 µg to 6mg of

hyperbaric bupivacaine increases the spread of analgesia, prolongs the time of first

analgesic requirement and decreases post operative pain, compared to bupivacaine

alone during inguinal herniorraphy under spinal anaesthesia and it does not

prolong the motor blockade when compared to 30 µg group.4

2)In a study done by Martin E, Ramsay G, Mantz J, Sum-Ping ST.

Dexmedetomidine was evaluated for sedation of 401 post surgical patients in a

double blind randomized, placebo controlled multicentre trial. 60%

dexmedetomidine patients required no other sedative to maintain RSS>/3. 21%

required <50mg propofol. In contrast 70% of the control group received propofol,

59% required >/50 mg propofol. 11

3)In a study done by Fragen RJ, Fitzgerald PC where the patients were given

dexmedetomidine or placebo infusion for at least 15 mins before anaesthetic

induction with sevoflurane in oxygen by face mask. After tracheal intubation a

target sevoflurane concentration was maintained for 15 minutes while the

dexmedetomidine or placebo infusion continued to run.It was seen that

dexmedetomidine 0.7ng/ml decreased the minimum alveolar concentration(MAC)

of sevoflurane by 17%,where as there was no difference between the placebo and

the dexmedetomidine 0.39ng/ml group. 10

4)In a study done by Gupta R, Bogra J, Verma R, Kohli M, Kushwaha J K,

Kumar S, it showed that 5µg dexmedetomidine seem to be an attractive alternative

as an adjuvant to spinal ropivacaine in surgical procedures, especially those

requiring long time. It has excellent quality of post operative analgesia with

minimal side effects.17

5) Mason et al observed increased incidence of hypertension in children <1yr,

undergoing magnetic resonance imaging (MRI) under dexmedetomidine sedation

and observed that younger children and multiple bolus therapies are highly

significant predictors of the occurrence of hypertension. 18

6) Sethi et al have studied the efficacy of low dose of intrathecal clonidine as

adjuvant to bupivacaine in gynaecological surgeries. They added 1µg/kg of

clonidine with 2.5ml of bupivacaine Vs plain bupivacaine. The duration of

anaesthesia was 614 minutes in clonidine group when compared to 223 minutes in

control group. Also the 2 segment regression time and the duration of motor

blockade was significantly prolonged in clonidine group. They concluded that by

adding clonidine the post operative analgesia is significantly prolonged with an

effect on sedation, heart rate and mean arterial pressure. 19

7) Philip.J.Siddall et al studied that the efficacy of intrathecal morphine and

clonidine in the treatment of pain after spinal cord injury. They demonstrated that

administration of a combination of morphine and clonidine into the spinal fluid

can provide substantial pain relief in some people with this type of pain. 20

6.3Aims and Objectives:

1)To compare the onset and duration of motor and sensory block,following

intrathecal bupivacaine with clonidine vs intrathecal bupivacaine with

dexmedetomidine in lower abdominal or lower limb surgeries

2)To compare hemodynamic changes and level of sedation, following intrathecal

bupivacaine with clonidine vs. intrathecal bupivacaine with dexmedetomidine in

lower abdominal or lower limb surgeries.

7. Materials and Methods.

7.1 Source of data collection:

The study group will comprise of patients admitted in KVG Medical College &

hospital, sullia, for elective lower abdominal or lower limb surgeries between

December 2011 and June 2013.

7.2 Method of data collection:

Inclusion Criteria Patients aged between 18-60 years

ASA I-III

Scheduled for elective lower abdominal or lower limb surgeries

Exclusion Criteria

Patients using α2-adrenergic receptors antagonists, calcium channel blockers, angiotensin converting enzyme inhibitors

Dysrhythmia

Body weight more than 120 Kg

Height less than 140 cm,

Post spinal surgeries, spinal deformity,

History of allergy to study drugs,

Pregnancy

Coagulopathy

Neurological disorders

Study design, sample size and sampling procedure:

A prospective, double blind, randomized, case control study on 150 patients.

Patients who are selected for the study will be randomly allocated to following three groups of 50 each

Group-B: 0.5% Bupivacaine 15mg + 0.5 ml Normal saline

Group-C: 0.5% Bupivacaine 15mg + 50 µg Clonidine

Group-D : 0.5% Bupivacaine 15mg + 5 µg Dexmedetomidine

Study procedure:

Following approval of the Ethical Committee of KVG Medical College & Hospital,

Sullia and obtaining written informed consent from patients, one hundred and fifty patients

belonged to ASA I-III, aged between 18-60 years scheduled for elective lower abdominal

or lower limb surgeries will be enrolled in the study,after pre anaesthetic check up.All

patients will be preloaded with 20ml/kg of Ringer’s Lactate solution via an 18 gauge IV

cannula in the dorsum of the hand. Standard anaesthesia monitoring will be used, including

non-invasive arterial blood pressure (NIBP), electrocardiography (ECG), heart rate (HR)

and pulse oximetry. Patient motor power and sensation to cold using alcohol solution will

be examined. With the patient in the sitting position, spinal anesthesia will be performed at

the level of L3-L4 through a midline approach using a 25-gauge Quincke spinal needle

(Becton Dickinson S.A, Madrid, Spain) with the bevel pointing upwards. If the spinal

block failed at the level of L3-L4, we will change the level to L2-L3.

Using a computer-generated random list, patients will be randomized to three groups

of fifty each: group B, C and group D. All patients will receive drug volume of 3.5ml

containing 3 ml hyperbaric bupivacaine hydrochloride (Neon laboratory, India) (15 mg).

Group B will receive 15 mg of 0.5% hyperbaric bupivacaine with normal saline

intrathecally, Group C will receive 15 mg of 0.5% hyperbaric bupivacaine with 50 µg of

clonidine(cloneon ®; 150μg/ ml Neon laboratory) and Group D will receive 15 mg of 0.5%

hyperbaric bupivacaine with 5 µg dexmedetomidine(dextomid®; 100μg/ ml Neon

laboratory). Injections will be made over 15-20 seconds. Patients, attending

anaesthesiologist and operating room personnel will be blinded to study. Thereafter,

patients will be placed in the supine position for surgery. No premedication will be given.

Heart rate (HR), mean arterial blood pressure (MAP) and oxygen saturation will be

monitored and recorded after the block every 5 minutes for half an hour then every 15

minutes until the end of surgery. The sensory block level will be assessed using loss of

temperature discrimination to alcohol solution along the midclavicular line bilaterally and

the higher level will used for statistical purposes if the levels were not the same bilaterally.

The motor block will be assessed using a modified Bromage scale. The time to reach T10

dermatome sensory block will be recorded before surgery. Sedation will be assessed using

Ramsay Sedation Scale (RSS) before the block and then every 15 min. Intravenous

midazolam will be allowed in increments of 1mg after the block if the patient is anxious.

After operation, HR, MAP, oxygen saturation, sedation score and VAS score at rest and

with movement will be recorded during the first hour at 15, 30, 45, and 60 min, and

thereafter every hour up to 8 h after spinal injection, then at 12 and 24 hours. The time

from intrathecal injection to two dermatome sensory regression, sensory regression to S1

dermatome and motor block regression to modified Bromage 0 will be recorded. All

durations will be calculated in relation to the time of spinal injection. Duration of pain

relief ,defined as the time from spinal injection to the first request for rescue analgesics

which will consist of intravenous infusion of diclofenac 75 mg that could be repeated after

12 h if needed with a maximum daily dose of 150 mg. Rescue doses of diclofenac will be

recorded. If satisfactory pain relief not achieved with diclofenac, additional analgesia will

be provided by oral or i.v tramadol 100 mg that could be repeated 4 hourly if needed with

maximum daily dose of 400mg.

Occurrence of nausea, vomiting, pruritus and respiratory depression will be recorded

throughout the study duration. Hypotension (defined as a decrease in systolic blood pressure

>30% of the baseline value or systolic blood pressure < 90 mm Hg) Will be treated with

intravenous boluses of 6mg ephedrine. Bradycardia defined as a pulse rate of < 50 beat/ min

will be treated with boluses of 0.3- 0.6 mg atropine. Respiratory depression (RR <8 or

SpO2<95%) will treated with oxygen supplementation and respiratory support if required.

All data collection will be performed by a blinded observer.

Follow up:

YES

Follow up period:

24 hours in postoperative ward

Statistical analysis:

The data will be analyzed using SPSS version 11.5 software for windows 7. t-test will

be used for Continuous data, and fisher’s exact test for non parametric data.

7.3 Does the study require any investigation\intervention to be conducted on

patients\ humans\ animals? If so, please describe briefly:

YES.

This study will be conducted on the 150 patients undergoing lower abdominal or

lower limb surgery under spinal anaesthesia with 15 mg of hyperbaric 0.5%

bupivacaine with or without 5 µg dexmedetomidine or 50 µg clonidine.

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

Yes. Copy of Ethical Committee Clearance attached.

8 REFERENCES.

1. Elia N, Culebras X, Mazza C, Schiffer E, Tramèr MR. Clonidine as an adjuvant to intrathecal local anesthetics for surgery: Systematic review of randomized trials. Reg Anesth Pain Med 2008;33:159-67.  

2. Boussofara M, Carlès M, Raucoules-Aimé M, Sellam MR, Horn JL. Effects of intrathecal midazolam on postoperative analgesia when added to a bupivacaine-clonidine mixture. Reg Anesth Pain Med 2006;31:501-5.

3. Sanders RD, Maze M: Alpha2-adrenoceptor agonists. Curr Opin Investig Drugs 2007; 8:25–33.

4. Dobrydnjov I, Axelsson K, Thorn S-E, et al. Clonidine combined with small-dose bupivacaine during spinal anesthesia for inguinal herniorrhaphy: a randomized double-blinded study. Anesth Analg 2003; 96: 1496–503.

5. Dobrydnjov I, Axelsson K, Samarutel J, Holmstrom B. Postoperative pain relief following intrathecal bupivacaine combined with intrathecal or oral clonidine. Acta Anaesthesiol Scand 2002; 46: 806–14.

6. De Kock M, Gautier P, Fanard L, Hody J, Lavand'homme P. Intrathecal ropivacaine and clonidine for ambulatory knee arthroscopy. Anesthesiology 2001; 94: 574–8.

7. Gordh T Jr, Post C, Olsson Y. Evaluation of the toxicity of subarachnoid clonidine, guanfacine, and a substance P-antagonist on rat spinal cord and nerve roots: light and electron microscopic observations after chronic intrathecal administration. Anesth Analg 1986; 65 (12): 1303–11.

8. Kanazi GE, Aouad MT, Jabbour-Khoury SI, Al Jazzar MD, Alameddine MM, Al-Yaman R, et al. Effect of low-dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block. Acta Anesthesiol Scand 2006;50:222-7.

9. Coursin DB, Maccioli GA. Dexmedetomidine. Curr Opin Crit Care 2001; 7: 221–6.

10. Fragen RJ, Fitzgerald PC. Effect of dexmedetomidine on the minimum alveolar concentration (MAC) of sevoflurane in adults age 55–70 years. J Clin Anesth 1999; 11: 466–70.

11. Martin E, Ramsay G, Mantz J, Sum-Ping ST. The role of the alpha2-

adrenoceptor agonist dexmedetomidine in postsurgical sedation in the intensive care unit. J Intensive Care Med 2000; 18: 29–34.

12. Kalso E, Poyhia R, Rosenberg P. Spinal antinociception by dexmedetomidine, a highly selective α2-adrenergic agonist. Pharmacol Toxicol 1991; 68: 140–3.

13. Savola M, Woodley J, Kendig J, Maze M. Alpha2B adrenoreceptor activation inhibits nociceptor response in the spinal cord of the neonatal rat. Eur J Pharmacol 1990; 183: 740.

14. Stevens C, Brenner G. Spinal administration of adrenergic agents produces analgesia in amphibians. Eur J Pharmacol 1996; 316: 205–10.

15. Asano T, Dohi S, Ohta S, Shimonaka H, Iida H. Antinociception by epidural and systemic alpha 2 adrenoreceptor agonists and their binding affinity in rat spinal cord and brain. Anesth Analg 2000; 90: 4.

16. Dobrydnjov.I.et al.Anaesthesia analgesia 2003;96:1496-503.17. Gupta R, Bogra J, Verma R, Kohli M, Kushwaha J K, Kumar S.

Dexmedetomidine as an intrathecal adjuvant for post operative analgesia.Indian J Anaesth 2011;55:347-51.

18. Mason KP, Zurakowski D, Zgleszewski S, Prescilla R,Fontaine PJ, Dinardo JA. Incidence and predictors of hypertension during high dose dexmedetomidine sedation for pediatric MRI. Paediatr Anaesth 2010;20:516-23.

19. Sethi S et al . Indian J Anaesth 2007;51(5):415-19.20. Philip.J.Siddall et al. Anaesthesia analgesia 2000;91:1493-98.

9 SIGNATURE OF CANDIDATE:

10. REMARKS OF THE GUIDE: TOPIC IS ABOUT A NEW DRUG,VERY NICE TOPIC,CAN BE APPROVED

11. 11.1 NAME AND DESIGNATION OF

11.1 Guide :

DR. SHANKARA NARAYANA P

ASSOCIATE PROFESSOR

DEPARTMENT OF ANAESTHESIOLOGY

K.V.G MEDICAL COLLEGE SULLIA.

11.2 Signature :

11.3 Head of the department:

11.4 Signature:

DR. GANAPATHY.P

PROFESSOR AND HOD

DEPARTMENT OF ANAESTHESIOLOGY

K.V.G MEDICAL COLLEGE SULLIA

12. 12.1 Remarks of the Principal:

12.2 Signature :

ETHICAL COMMITTEE CLEARANCE

1.TITLE OF

DISSERTATION

A COMPARATIVE STUDY OF EQUIPOTENT DOSES OF INTRATHECAL CLONIDINE AND DEXMEDETOMIDINE ON

CHARACTERISTICS OF BUPIVACAINE SPINAL BLOCK

2.NAME OF THE CANDIDATE

Dr. JAHNABEE SARMA

3. NAME OF THE

GUIDE

Dr. SHANKARA NARAYANA P

4. APPROVED / NOT APPROVED

Sri KRISHNAMURTHY ,Chairperson

Dr. SUBBANNAYYA KOTI GADDE, Secretary.

Dr. S. GOPAL RAO , Member

Dr. C. S. MOHANRAJ , Member

Dr. H. R. SHIVAKUMAR , Basic scientist

LAW EXPERT : Sri KRISHNAMURTHY , Advocate

PRINCIPAL

K.V.G. Medical College and Hospital , Sullia.

PROFORMA INFORMED CONSENT

I Dr.JAHNABEE SARMA .PG Department of anaesthesia conducting a randomized trial for award of MD degree in Anaesthesia.

The topic of the study is:

A COMPARATIVE STUDY OF EQUIPOTENT DOSES OF INTRATHECAL CLONIDINE AND DEXMEDETOMIDINE ON CHARACTERISTICS OF BUPIVACAINE SPINAL BLOCK

Objectives:

1) To compare the onset and duration of motor and sensory block,following intrathecal bupivacaine with clonidine vs intrathecal bupivacaine with dexmedetomidine in lower abdominal or lower limb surgeries

2)To compare hemodynamic changes and level of sedation, following intrathecal bupivacaine with clonidine vs. intrathecal bupivacaine with dexmedetomidine in lower abdominal or lower limb surgeries

I have been briefed on the foregoing research being conducted by Dr.Jahnabee Sarma and it has been conveyed to me in my own language .I have had the opportunity to ask questions about it & all questions that I have asked have been answered to my satisfaction.I consent voluntarily to participate as a participant in this research & understand that I have the right to withdraw from the research at any time without in any way affecting my medical care.

Name of the participant:………………………………………………………

Signature o the participant:……………………………………………………

Date:(d/m/y)…………………………………………………………………..

If illiterate

A literate witness must sign( If possible this person should be selected by the participant and should have no connection to the research team)

I have read and witnessed the accurate reading of the consent form to the potential participant and the individual has had the opportunity to ask questions,I confirm that the individual has given consent freely

Name of the witness : ………………................................

Signature of the witness:…………………………………...

Date:(d/m/y)………………………………………………

Thumb impression of participant

I have read and witnessed the accurate reading of the consent form to the potential participant and the individual has had the opportunity to ask questions,I confirm that the individual has given consent freely. In case of any doubt I have been asked to contact :

Dr.JAHNABEE SARMA

PG. ANAESTHESIA

K.V.G.MEDICAL AND HOSPITAL.SULLIA.574327

CONTACT NO: 9880426681.

Name of Researcher:………………………………………………………….

Signature of researcher:……………………………………………………..

Date :( d/m/y)…………………………………………………………………….

A copy of this informed consent form has been provided to participant …………………………………………………………………after initialed by the Researcher.

PROFORMA

A COMPARATIVE STUDY OF EQUIPOTENT DOSES OF

INTRATHECAL CLONIDINE AND DEXMEDETOMIDINE ON CHARACTERISTICS OF BUPIVACAINE SPINAL BLOCK

Name :

Age/Gender :

IP. Number:

Ward/SU :

Date of surgery:

ASA Physical status:

Co morbidity :

Patient on any drugs :

Group (Tick any one)

Group-B: 0.5% Bupivacaine. 15mg + 0.5ml Normal saline

Group-C: 0.5% Bupivacaine 15mg + 50 µg Clonidine

Group -D: 0.5%Bupivacaine.15mg+ 5 µg Dexmedetomidine

Patient position:

Duration of surgery :

Medications :

Inj. Atropine 0.3-0.6mg i.v if PR< 50/min

Inj. Ephedrine 6 mg Intermittent bolus If MAP < 90 mmHg

Respiratory depression (RR <8 or SPo2<95%); Oxygen supplementation and respiratory support if required

OBSERVATIONS:

Intraoperative haemodynamics:

TIME SpO2 RR MAP Heart rate

Pre-Operative

5 Min. after SAB¶

10 Min. after SAB. ¶

15 Min. after SAB. ¶

20 Min. after SAB¶.

25 Min. after SAB. ¶

30 Min. after SAB. ¶

45 Min. after SAB. ¶

1hr, after SAB. ¶

1hr. 15 Min. after SAB¶

1hr 30 Min. after SAB¶.

2hrs. after SAB. ¶

2hrs. 30 Min. after SAB¶.

3hrs. after SAB. ¶

3hrs30 Min. after SAB. ¶

4hrs. after SAB. ¶

4hrs30 Min. after SAB. ¶

5hrs. after SAB. ¶

5hrs 30 Min. after SAB. ¶

¶ SAB-sub arachnoid block

Post operative haemodynamics:

TIME SpO2 RR MAP Heart rate

Post

Operative

15Min.

30min.

45min.

60min.

2hrs

3hrs

4hrs

5hrs

6hrs

7hrs

8hrs

12hrs

24hrs

Sensory blockade* :

Time 5 min 10 min 15 min 20 min

Sensory level

*By loss of temperature discrimination to alcohol every 5 minutes till it reaches the highest level

Motor blockade (Bromage scale)*:

Time 5 min 10 min 15 min 20 min

Motor level

*By Bromage scale every 5 minutes till it reaches the grade 4

*Bromage scale

1- Free movement of legs / feet

2- Just able to flex knees with free movement of feet

3- Unable to flex knees, but with free movement of feet

4- unable to move legs/ feet

Sedation score:(Ramsay Sedation Scale (RSS)*:

Time Sensory level

Before surgery

15 min. after SAB¶

30 min. after SAB¶

45 min. after SAB¶

60 min. after SAB¶

1hr after SAB¶

2hrs after SAB¶

3hrs after SAB¶

4hrs after SAB¶

5hrs after SAB¶

6hrs after SAB¶

¶ SAB-sub arachnoid block

Ramsay Sedation Scale*

0- Fully awake

1- drowsy

2- drowsy but arousable to touch / call

3- drowsy but arousable on deep stimuli

Post operative pain score (Visual analog scale)*:

Time Pain score

15 min.

30 min.

45 min.

1 hour

2 hour

3 hour

4 hour

5 hour

6 hour

7 hour

8 hour

12 hour

24 hour

Visual analog scale*

Pain Intensity Word Scale

0 No pain

1-2 Least pain

3-4 Mild pain

5-6 Moderate pain

7-8 Severe pain

9-10 Excruciating pain

Pain score >5 – supplementary analgesia given

Different time intervals:

Time of sub arachnoid block

Time to reach highest level of sensory blockade

Time to obtain grade 4 motor block(Bromage scale)

Time to reach 2-segment regression

Time for Sensory regression to S1 dermatome

Time for Motor block regression to S1 dermatome

Time of rescue analgesia